Methods and compositions for increasing feed intake of animals using tertiary alcohols

ABSTRACT

New methods and compositions for inducing polyphagia in growing or fattening meat producing animals such as sheep or cattle are described using as active ingredients tertiary alcohols or the corresponding carbamates, ureas, oxyureas or ureides. The active ingredients are used most usefully at sub-hypnotic quantities admixed in animal feed.

.Iadd.This application is a reissue of U.S. Pat. No. 3,852,473 issuedDec. 3, 1974 from Ser. No. 328,235 filed Jan. 31, 1973. .Iaddend.

This invention relates to animal feed compositions and to novel methodsof increasing the feed intake of growing or "fattening" animals byadministering as the active ingredients in these compositions andmethods certain tertiary alcohols and derivatives thereof. Morespecifically, this invention relates to a method of increasing feedintake in immature animals beyond satiety by administering internallythe active ingredient, a tertiary alcohol or derivative thereof, as suchor distributed uniformly in the feed of the animals. Oral or implantadministration is preferred from a practical viewpoint.

Increasing the feed intake in meat producing animals, particularlyruminants, is an important commercial objective. Immature sheep andcattle are commonly fed for maximum growth rate in feed lots until theyreach a marketable weight. When the desired weight is achieved, theanimal is sold for slaughter. There is a normal feed intake for mostanimals due to both physical and metabolic factors. Animals becomenaturally satiated and thereafter will not feed voluntarily until thehunger drive again becomes dominant.

It has been unexpectedly found that, when certain tertiary alcohols ortheir urea, ureide, oxyurea or carbamate derivatives are administered toanimals, polyphagic activity is induced, i.e., they eat more and gainweight at a faster rate resulting in better overall efficiency to thegrower.

The practical effect of this invention is to induce meat producinganimals, preferably sheep or cattle, to eat past the point of satiety orto induce polyphagia in the immature animal by administering internally,preferably by implant or orally, the active ingredients of thisinvention. The active ingredients are most conveniently disperseduniformly throughout the normal feed of the subject animal in effectivebut nontoxic quantities.

The increased feed intake and concomitant weight gain of animals isaccomplished in accordance with this invention by a method whichcomprises administering internally to the animal a compound of thefollowing basic structure formula: ##EQU1## in which:

R is lower alkyl of from 1-9, preferably 1-5, carbon atoms or hydroxylower alkyl of from 1-9, preferably 2-5, carbon atoms;

R' is lower alkyl of from 1-9, preferably 1-5, carbon atoms, or halosuch as fluoro, chloro or bromo;

R" is lower alkyl of from 1-9, preferably 1-5, carbon atoms, loweralkenyl of from 2-9, preferably 2-5, carbon atoms, lower alkynyl of from2-9, preferably 2-5, carbon atoms and, when R and R' are hydrogen orlower alkyl, phenyl; and,

X is --OH, --NHCONH₂ (ureido), --ONHCONH₂ (oxyureido), --OCONH₂(oxycarbamyl) or --CONHCONH₂ (carbonylureido).

A preferred group are those compounds of Formula I in which R, R' and R"are lower alkyl of from 1-5 carbon atoms. It will be recognized thatcertain of the active ingredients are not truly "tertiary alcohols" butthis generic term is most conveniently used to describe the inventionbecause the tertiary alcohols are the nub of the invention.

One skilled in the medicinal art will recognize that certain of thebasic compounds of Formula I have been known to have medicinal effectsin humans, especially hypnotic effects, such as phenylacetyl urea;3-methyl-1-pentyne-3-ol [Meparfynol], carbamic acid1-ethyl-1-methyl-2-propynyl ester [Meparfynol carbamate],(α-bromo-α-ethylbutyryl)-urea [Carbromal] and 1-ethyl-1-1-methylpropylcarbamate [Emylcamate]. In the compositions and methods of thisinvention, the quantities of active ingredients are much below thehypnotic effect in animals, especially on a dose per unit of body weightbasis. In fact, if the dose approaches the hypnotic effect, the veryopposite action may be achieved, that is, the animal may becomedisinterested in food because of a general central nervous systemdepression. If sleepy or sedated the animal will not eat enough tosatisfy its appetite and certainly not enough to cause a polyphagiceffect. This effect has been noted in the test data presented hereafter.Therefore, in the context of this disclosure an overt pharmacodynamic ortherapeutic effect such as hypnosis or sedation is classified as a toxiceffect.

It will be recognized therefore that the active ingredients of thisinvention are old compounds known to the art. The tertiary alcohols areusually liquids and in the formulation of premixes or supplemented feedsthis must be taken into account using standard techniques of the art.The alcoholic derivatives, for example the ureas, oxyurea, acylureas(ureides) or carbamates, are particularly useful because of their solidor crystalline state. The compounds which are the basis of thisinvention are notable for their very low chemical cost. Certain membersof the groups are by-products of fermentation or chemical syntheticprocedures.

Among the individual compounds most useful in the invention arebenzyloxyurea, 1-ethyl-1-methylpropyl carbamate, 3-methyl-3-pentanol,1-ethyl-1-methyl propyloxyurea, N-(1-ethyl-1-methylpropyl)urea,3-methyl-1-pentyne-3-ol, carbamic acid 1-ethyl-1-methyl-2-propynyl esterand (α-bromo-α-ethylbutyryl)-urea. The solid nitrogen derivedderivatives are preferred.

The compounds can be administered to growing meat producing animalsintramuscularly or subcutaneously in the form of solutions for injectionor preferably pellet implants. Most usually, the compounds can be mixedwith conventional animal feed compositions. The feed compositions arethen fed to ruminant or monogastric animals, according to methods wellknown to the agricultural art. The compounds are particularlyadvantageous when incorporated into the normal feeds of meat producinganimals. Preferably the compounds are incorporated into fatteningruminant feeds.

The animal feeds most generally used in conjunction with the method ofthis invention are either various grain mixtures and/or roughage feedssuch as hay commonly fed to meat producing animals especially cattle orsheep feeds. The amount of additive used to supplement such feeds willbe in an amount sufficient to induce polyphagia, i.e., to increase feedintake and/or thereby to improve the feed efficiency of the animal butnot to have a toxic or noxious effect; within the broad range of fromabout 10 g. to 2 kg. per ton of feed, preferably from about 100 g. toabout 1 kg./ton. An average sheep will ingest about 3-4 lbs. of feeddaily; an average feed lot steer about 20-25 lbs. Therefore, thepreferable broad range of dosage for ruminants by any method of internaladministration will range approximately from 50 mg. to 10 g. per daydepending on the potency of the ingredient for these purposes. It willbe appreciated that the exemplary dose ranges given are for a genericgroup of chemical compounds having varying potencies. The gist of theinvention claimed is that certain sub-therapeutic or sub-hypnoticquantities of the chemical compounds administered as described have apolyphagic effect.

For commercial use, the active ingredients usually are most readily usedas premix formulations in which the chemical is distributed uniformlythroughout a standard animal organic or inorganic feed carrier in aconcentrated form which is conveniently packaged and shipped to the feedmixer. This premix or concentrate is then in turn mixed uniformly with anormal diet for the animal as desired by the grower or the feed mixer.Examples of such carriers for premix compositions are soybean meal, cornoil, ground corn, barley, wheat, mineral mixtures such as vermiculite,diatomaceous earth, corn gluten meal, corn distillers solubles orsoyflour. The active ingredient will be in amounts to satisfy thecriteria set forth above for whole feed. The active ingredient willusually be present in from about 1-75 percent by weight of the premixcomposition.

If the ingredients are liquids or unstable materials, they mayoptionally be adsorbed on silica, kieselguhr, etc. or coated with asolid, absorbable fat or resin by standard spray drying or congealingtechniques (See U.S. Pat. No. 3,660,562).

The animal feeds themselves may also contain roughages such ascellulose, hay, straw, silages, corn stalks, cotton seed hulls, oats,barley and cereal brans; natural oils such as animal fats, fish oils,safflower oil, peanut oil, and cottonseed oil; antioxidants, minerals,vitamins, antibiotics, anthelmintics; and other appropriate medicaments.

Examples of typical prepared animal feed is as follows:

EXAMPLE 1

    Ingredients      Weight percent                                               ______________________________________                                        Mixed hay        40.0                                                         Ground yellow corn                                                                             45.0                                                         Soybean oil meal 7.0                                                          Cane molasses    7.0                                                          Dicalcium phosphate                                                                            0.5                                                          Trace minerals salt                                                                            .5                                                           Vitamin A        300 I.U./lb.                                                 Vitamin D        150 I.U./lb.                                                 1-ethyl-1-methylpropyl                                                                         1 lb./ton of feed                                            carbamate                                                                     ______________________________________                                    

EXAMPLE 2

An example of a suitable premix is as follows:

    N-(1-ethyl-1-methylpropyl)-urea                                                                    2 lb.                                                    Ground yellow corn   to 10 lbs.                                           

EXAMPLE 3

In the field the active ingredients may be administered by means of saltor molasses blocks. A typical block may be prepared using the followingconditions:

    Ingredients       Weight percent                                              ______________________________________                                        Dried cane molasses                                                                             29.5                                                        Ground soybean hulls                                                                            24.90                                                       3-Methyl-3-pentanol                                                                             20.00                                                       Granulated salt   21.59                                                       Trace minerals and vitamins                                                                     0.20                                                        Stabilized animal fat                                                                           1.11                                                        Moisture          2.66                                                        ______________________________________                                    

EXAMPLE 4 -- Cattle Diet

    Ingredients         Weight percent                                            ______________________________________                                        Ground shelled corn 65.85                                                     Mixed ground hay    20.00                                                     Dried molasses      6.00                                                      Soybean meal        6.00                                                                          1.5 lb./ton -    feed                                     3-Methyl-1-pentyne-3-ol                                                                           .55                                                       Trace mineral salt  .50                                                       Dicalcium phosphate .40                                                       Ground limestone    .70                                                       Vitamin A (30,000 units/gms.)                                                                     66.7 gm./ton                                              Vitamin D.sub.2 (16,000,000 units/lb.)                                                             7.1 gm./ton                                              ______________________________________                                    

The method of this invention comprises allowing the cattle or sheep tograze or be fed ad libitum on the supplemented rations or to be fed on aregular schedule.

EXAMPLE 5 -- Implant Pellets

    Ingredients      Amount                                                       ______________________________________                                        Phenylacetylurea 100 mg.                                                      Calcium sulfate, dihydrate                                                                     20 mg.                                                       Gelatin          4 mg.                                                        Magnesium stearate                                                                             1 mg.                                                        Talc             2 mg.                                                        ______________________________________                                    

The phenylacetylurea and calcium sulfate, dihydrate are mixed and passedthrough a No. 40 standard mesh screen. The screened mixture is thengranulated with hot 15 percent gelatin solution, screened through a No.10 mesh screen and dried overnight at 120°F. The granules are againscreened through a No. 40 mesh screen and mixed with the magnesiumstearate and talc. The granules are compressed into implants using a 1/8inch flat face punch and die. One implant is administeredintramuscularly.

EXAMPLE 6 -- Screening Tests

A qualitative test for polyphagic activity is the two hour peripheral(i.v.) injection test. The protocol for this test and representativetest results follow.

The active ingredient was tested in 8 sheep or 8 cattle weighing 50-60and 200-300 kg., respectively. Feed and water were available ad libitum.

A control of dimethylsulfoxide (DMS) was maintained. The procedurecomprised;- 60 min. weigh feed, 0 min. inject chemical in 1.5 ml. DMSfor sheep and 5.0 ml. for cattle intravenously then weigh feed. Theresult is entered as a percent of Control Intake, of course the controlbeing 100 percent.

                                      SHEEP                                       __________________________________________________________________________    R     R'     R"        X     Dose(mg.)                                                                            %(120 min.)                               __________________________________________________________________________    C.sub.2 H.sub.5                                                                     Br     C.sub.2 H.sub.5                                                                       CONHCONH.sub.2                                                                        31     142                                                                    62     164                                                                    125    136                                                                    500    77                                        C.sub.2 H.sub.5                                                                     CH.sub.3                                                                             C.tbd.CH                                                                              OH      31     100                                                                    62     164                                                                    125    148                                                                    500    226                                       CH.sub.3                                                                            CH.sub.3                                                                             C.tbd.CH                                                                              OH      31     110                                                                    62     97                                                                     125    130                                                                    500    70                                        (n)C.sub.5 H.sub.11                                                                 CH.sub.3                                                                             C.tbd.CH                                                                              OH      62     104                                                                    125    157                                                                    500    0                                         C.sub.2 H.sub.5                                                                     CH.sub.3                                                                             C.sub.2 H.sub.5                                                                       OH      62     138                                                                    125    154                                                                    300    185                                                                    600    127                                       C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                      CH.sub.3                                                                              OCONH.sub.2                                                                           62     146                                                                    125    203                                                                    250    193                                                                    500    319                                                                    750    272                                       CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3                                                                              OCONH.sub.2                                                                           500    109                                                                    1500   139                                       CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3                                                                              NHCONH.sub.2                                                                          250    129                                       CH.sub.3                                                                            CH.sub.3                                                                             C.sub.6 H.sub.5                                                                       OH      62     66                                                                     125    131                                                                    500    88                                        H     H      C.sub.6 H.sub.5                                                                       CONHCONH.sub.2                                                                        31     123                                                                    62     144                                                                    125    167                                                                    200    141                                                                    500    133                                       H     H      C.sub.6 H.sub.5                                                                       ONHCONH.sub.2                                                                         300    122                                       H     H      C.sub.6 H.sub.5                                                                       OCONH.sub.2                                                                           125    133                                                                    250    73                                        H     CH.sub.3                                                                             iso-C.sub.4 H.sub.9                                                                   OH      125    85                                                                     500    127                                                                    823    77                                        iso-C.sub.3 H.sub.7                                                                 CH.sub.3                                                                             CH.sub.3                                                                              OH      125    105                                                                    500    123                                       C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                       OH      125    124                                                                    500    143                                       CH.sub.3                                                                            CH.sub.3                                                                             C.sub.2 H.sub.5                                                                       OH      125    123                                                                    500    172                                       CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.sub. 4 H.sub.9                                                                      OH      31     95                                                                     125    115                                       CH.sub.3                                                                            CH.sub.3                                                                             C.sub.4 H.sub.9                                                                       OH      62     71                                                                     125    121                                                                    500    50                                        CH.sub.3                                                                            CH.sub.3                                                                             C.sub.5 H.sub.11                                                                      OH      31     148                                                                    62     91                                                                     125    109                                       2-    CH.sub.3                                                                             CH.sub.3                                                                              OH      62     56                                        (OH)C.sub.3 H.sub.6          125    144                                                                    500    126                                       CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.2 =CH.sub.2 CH.sub.2                                                           OH      62     99                                                                     125    151                                                                    250    155                                       CH.sub.3                                                                            iso-C.sub.3 H.sub.7                                                                  C.sub.2 H.sub.5                                                                       OH      62     144                                                                    125    195                                                                    500    104                                       CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 C.tbd.C                                                                      OH      125    103                                                                    500    211                                                                    1000   166                                       CH.sub.3                                                                            CH.sub.3                                                                             C.sub.2 H.sub.5                                                                       NHCONH.sub.2                                                                          250    110                                                                    500    106                                       CH.sub.3                                                                            CH.sub.3                                                                             iso-C.sub.4 H.sub.9                                                                   OH      62     104                                                                    125    145                                                                    500    38                                        CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      CH.sub.2 =CH                                                                          OH      125    123                                                                    500    160                                                                    100    78                                        iso-C.sub.3 H.sub.7                                                                 iso-C.sub.3 H.sub.7                                                                  CH.tbd.C                                                                              OH      62     110                                                                    125    170                                       C.sub.2 H.sub.5                                                                     ClCH=CH                                                                              CH.tbd.C                                                                              OH      31     45                                                                     62     160                                                                    125    105                                       CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      CH.tbd.C                                                                              OCONH.sub.2                                                                           31     112                                                                    62     54                                                                     125    139                                       CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                       NHCONH.sub.2                                                                          62     153                                                                    125    147                                                                    250    221                                                                    500    142                                       CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      BrC=CBr OH      62     85                                                                     125    162                                                                    500    119                                       CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      CH.tbd.CC.sub.5 H.sub.10                                                              OH      125    150                                                                    500    78                                        __________________________________________________________________________

EXAMPLE 7 -- Secondary Tests

                                      CATTLE                                      __________________________________________________________________________    R     R'     R"     X      Dose(mg.)                                                                            %(120 min.)                                 __________________________________________________________________________    CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                     OCONH.sub.2                                                                           625    133                                                                    1250   128                                         H     H      C.sub.6 H.sub.5                                                                     ONHCONH.sub.2                                                                         1000   113                                         H     H      C.sub.6 H.sub.5                                                                     CONHCONH.sub.2                                                                        250    103                                                                    375    77                                                                     375    270                                                                    750    165                                                                    1500   100                                                                    1500   179                                                                    150    108                                         CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                     OH      1250   84                                                                     1500   103                                                                    2500   100                                                                    3750   149                                         CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                     NHCONH.sub.2                                                                          300    80                                                                     600    87                                                                     1250   113                                                                    1250   117                                         CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      C.tbd.CH                                                                            OH      1250   154                                         C.sub.2 H.sub.5                                                                     Br     C.sub.2 H.sub.5                                                                     CONHCONH.sub.2                                                                        625    100                                                                    1250   94                                                                     2500   129                                         iso-C.sub.3 H.sub.7                                                                 iso-C.sub.3 H.sub.7                                                                  C.tbd.CH                                                                            OH      1250   102                                         CH.sub.3                                                                            CH.sub.3                                                                             C.sub.6 H.sub.5                                                                     OH      1250   120                                         __________________________________________________________________________

We claim:
 1. The method of increasing feed intake in an immatureruminant animal subject comprising administering orally or by implant tosaid animal subject a quantity effective for increasing feed intake butnontoxic to the subject of a tertiary alcohol having the formula:RR'R"CXin which: R is lower alkyl of from 1-9 carbons or hydroxy lower alkyl offrom 1-9 carbons; R' is lower alkyl of from 1-9 carbons, fluoro, bromoor chloro; R" is lower alkyl of from 1-9 carbons, lower alkenyl of from2-9 carbons.Iadd., lower alkynyl of from 2-9 carbons .Iaddend.and, whenR and R' are lower alkyl or hydrogen, .Iadd.R" is .Iaddend.phenyl; and Xis --OH.
 2. The method of claim 1 in which R, R' and R" are lower alkylof from 1-5 carbons.
 3. The method of claim 1 in which the animal issheep or cattle.
 4. The method of claim 2 in which the subject animal issheep or cattle.
 5. The method of claim 1 in which the internaladministration is orally and admixed with the animal feed.
 6. The methodof claim 5 in which the quantity of tertiary alcohol derivative is fromabout 10 g.-2 kg. per ton of feed.
 7. The method of claim 5 in which thequantity of tertiary alcohol derivative is about 50 mg.-10 g. per animalsubject.
 8. A ruminant animal feed composition comprising an animal feedcarrier supplemented by a quantity of active ingredient effective forincreasing feed intake but nontoxic to the animal, said activeingredient being a tertiary alcohol derivative of the formula:RR'R"CX inwhich: R is lower alkyl of from 1-9 carbons or hydroxy lower alkyl offrom 1-9 carbons; R' is lower alkyl of from 1-9 carbons, fluoro, bromoor chloro; R" is lower alkyl of from 1-9 carbons, lower alkenyl of from2-9 carbons.Iadd., lower alkynyl of from 2-9 carbons .Iaddend.and, whenR and R' are lower alkyl or hydrogen R" is phenyl; and X is --OH.
 9. Thefeed composition of claim 8 in which the said active ingredient is atertiary alcohol of the formula:RR'R"COH in which R, R' and R" are loweralkyl of 1-5 carbons.
 10. The feed composition of claim 1 in which thesaid composition is a whole feed adapted for fattening immature ruminantanimals.
 11. The feed composition of claim 8 in which the saidcomposition is a premix composition adapted for mixing uniformlythroughout a whole animal feed adapted for fattening immature ruminantanimals.
 12. The feed composition of claim 10 in which the activeingredient is present within the range of from about 100 g. to 2 kg. perton of feed.
 13. The feed composition of claim 11 in which the activeingredient is present at the rate of about 1-75 percent by weight. 14.The feed composition of claim 9 in which the active ingredient ispresent within the range of from about 100 g. to 2 kg. per ton of feed.